Epidemiology and etiology of premenopausal osteoporosis

INTRODUCTION — Osteoporosis is a skeletal condition characterized by low bone mass, which is associated with reduced bone strength and an increased risk of fractures. Osteoporosis occurs most commonly in postmenopausal women. Numerous guidelines and recommendations exist regarding the evaluation and management of osteoporosis in this population. Male osteoporosis has also gained attention as a growing public health concern. Postmenopausal osteoporosis and osteoporosis in men are reviewed separately. (See "Clinical manifestations, diagnosis, and evaluation of osteoporosis in postmenopausal women" and "Overview of the management of low bone mass and osteoporosis in postmenopausal women" and "Etiology of osteoporosis in men".)

Both fractures and low bone mass are less common in premenopausal women. Low bone mass, when present, may be related to either inadequate peak bone mass acquisition and/or ongoing bone loss. Bone loss and/or fractures can often be attributed to a secondary cause such as estrogen deficiency, glucocorticoid exposure, or hyperparathyroidism. The term idiopathic osteoporosis (IOP) is reserved for the subset of women with no apparent etiology or known secondary cause. Some women with IOP may have an adult presentation of a primary or genetic etiology of bone fragility [1,2].

The diagnosis of osteoporosis and guidelines for treatment of osteoporosis based upon bone mass in postmenopausal women do not generally apply to premenopausal women, as the relationship between bone mass and fracture risk in premenopausal women is not the same as in postmenopausal women.

This topic reviews the definition, epidemiology, and etiology of premenopausal osteoporosis. Evaluation and management will be reviewed separately. (See "Evaluation and treatment of premenopausal osteoporosis".)

DEFINITIONS

Low bone mass — The measurement of bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA) is used as an index of bone strength and fracture risk, and it can be used to diagnose osteoporosis in some populations, such as postmenopausal women. The World Health Organization (WHO) defines osteoporosis in postmenopausal women as a BMD value at the spine, hip, or forearm of 2.5 or more standard deviations (SD) below the young adult mean (T-score ≤-2.5), with or without the presence of a fragility fracture [3]. (See "Clinical manifestations, diagnosis, and evaluation of osteoporosis in postmenopausal women" and "Overview of dual-energy x-ray absorptiometry".)

In premenopausal women, the prevalence of fractures is much lower compared with postmenopausal women, and the relationship between BMD and fracture risk is not the same. Thus, neither the diagnostic guidelines nor the treatment practices based on BMD measurements in postmenopausal women can apply to this younger population. Similarly, the Fracture Risk Assessment (FRAX) tool cannot be used to evaluate fracture risk based on BMD in premenopausal women. The International Society for Clinical Densitometry (ISCD) recommends use of BMD Z-scores (comparison with age-matched norms) at the lumbar spine, total hip, femoral neck, and distal radius, rather than T-scores, and avoidance of the term osteopenia [4]. The use of Z-scores in this population helps to avoid application of the postmenopausal diagnostic and therapeutic implications of the T-score. A Z-score ≤-2.0 should be interpreted as "below the expected range for age" [4]. (See "Clinical manifestations, diagnosis, and evaluation of osteoporosis in postmenopausal women" and "Overview of dual-energy x-ray absorptiometry".)

BMD measurements alone should not be used to define osteoporosis in premenopausal women [5,6]. According to the ISCD, a young woman with low BMD for age (Z-score ≤-2.0) and with risk factors for fracture or secondary causes of osteoporosis (such as glucocorticoid therapy, hypogonadism, or hyperparathyroidism) may be defined as having premenopausal osteoporosis [4]. However, in contrast to ISCD, the International Osteoporosis Foundation (IOF) recommends use of T-scores in those aged 20 to 50 years and suggests use of T-score <-2.5 to define osteoporosis, particularly in those with known secondary causes or in the context of low-trauma fractures that provide evidence of bone fragility [7].

Low-trauma fracture — Premenopausal women may come to medical attention because of a fragility fracture. As in all cases of unusual fracture, the diagnosis of osteoporosis should be considered only after osteomalacia (undermineralization due to causes such as severe vitamin D deficiency or hypophosphatemia) and other causes of pathological fracture (eg, malignancy, avascular necrosis, fibrous dysplasia, other bone lesion) have been ruled out. After ruling out these pathologies, any fracture in an adult woman (aside from a fracture of the digits, skull, or face) that occurs from a standing height or less, without major trauma such as a motor vehicle accident, can be considered a low-trauma or fragility fracture. Such women may have decreased bone strength. Premenopausal women with a history of low-trauma fracture at sites such as the spine, hip, pelvis, humerus, or forearm may be considered to have osteoporosis, irrespective of BMD.

EPIDEMIOLOGY

Low bone mass — Low bone mass is less common in premenopausal women compared with postmenopausal women and, when present, may be related to either inadequate peak bone mass acquisition, or previous or continuing bone loss.

The clinical significance of isolated low bone density (without fracture) in young women is unknown. Some premenopausal women with low bone mineral density (BMD), particularly those with a known secondary cause of osteoporosis, may have abnormal bone strength that may lead to an increased risk of fracture. Currently, available data do not allow us to predict fracture risk in premenopausal women with low bone density and no known secondary cause. One longitudinal study has documented stable BMD and a low short-term risk of fractures in this population [8]. However, in a study of premenopausal women with idiopathic osteoporosis (IOP; unexplained low BMD or low-trauma fracture), high-resolution peripheral quantitative computed tomography (HRpQCT) [9] and analyses of transiliac biopsy samples [10] showed comparable microarchitectural deterioration in the low BMD and fracture groups compared with controls [9]. These findings suggest that asymptomatic low BMD is associated with structural abnormalities that would predict lower bone strength. Even so, because of a lack of prospective data relating BMD to fracture risk, BMD alone cannot be used to determine osteoporosis diagnosis or treatment in premenopausal women.

Peak bone mass acquisition — BMD in premenopausal women depends primarily upon achievement of peak bone mass. Low BMD in a premenopausal woman may result from the attainment of a peak bone mass that is below average due to genetic predisposition, illnesses, or medications that negatively impact bone density accrual. "Peak bone mass" is usually defined as the maximum BMD achieved by age 30 to 40 years, as measured by dual-energy x-ray absorptiometry (DXA) [11,12].

In healthy girls, the peak period of bone mass accrual occurs between ages 11 and 14 years [13]. Although 95 to 100 percent of peak bone mass is acquired by the late teen years [13-15], studies have documented continued small gains occurring between the ages of 20 and 29 years [16]. Population-based, cross-sectional studies suggest that women attain peak bone mass at the proximal femur in their 20s and at the spine and forearm around age 30 years [17,18].

Attainment of peak bone mass varies according to sex, ethnicity, body size, and region of bone [12]. Thus, when interpreting BMD measurements in premenopausal women, the possibility that peak bone mass has not yet been achieved must always be considered. (See "Pathogenesis of osteoporosis", section on 'Peak bone mass acquisition'.)

Perimenopausal bone loss — Bone loss begins prior to menopause, as illustrated by several prospective studies [19-28] that have reported varying degrees of bone loss during the menopausal transition, more often in women with subclinical ovulation disturbances or perimenopausal symptoms [29,30].

In a longitudinal, multiethnic cohort study of 862 women followed for 10 years, the annual rates and cumulative amounts of BMD loss were greater one year prior through two years after the final menstrual period (transmenopause) than those occurring between two and five years after the final menstrual period (postmenopause) [31]. Cumulative 10-year and transmenopause BMD loss was 10.6 and 7.4 percent, respectively, at the lumbar spine and 9.1 and 5.8 percent, respectively, at the femoral neck. Higher body mass index (BMI) was associated with slower bone loss. The adverse effect of low body weight on bone loss during the menopausal transition was similarly reported in a study of 896 perimenopausal women followed for a mean of six years [32].

Fractures

Relationship to BMD — Premenopausal women generally have much lower rates of fracture than postmenopausal women [33-37]. As in postmenopausal women, however, young women with lower BMD tend to have the greatest risk for fractures [38-40]. In two studies of premenopausal women with Colles' fractures, BMD at the nonfractured radius [41], lumbar spine, and femoral neck [42] were significantly below age-matched peers. In another study comparing premenopausal women with a distal radius fracture with controls, BMD (DXA) was similar at these sites; however, there was evidence of trabecular microarchitectural deterioration (as measured by HRpQCT) at both the distal radius and distal tibia in the women with fracture [43]. Stress fractures, a distinct fracture type associated with repeated mechanical stress, rather than acute injury, are particularly common among certain groups of young women including professional dancers, military recruits, and female athletes. Stress fractures have been associated with lower BMD in some studies [44-52], but not others [53]. Studies using analyses of images obtained via HRpQCT of the radius and tibia have also documented trabecular microarchitectural deficiencies in premenopausal women with fractures, in comparison with controls [54-56]. (See "Overview of stress fractures" and "Functional hypothalamic amenorrhea: Pathophysiology and clinical manifestations".)

Vertebral fractures can occur despite normal BMD in women receiving glucocorticoids. One study found that 7 of 16 premenopausal women treated with high-dose glucocorticoids had evidence of vertebral fractures despite normal BMD [57]. Vertebral fractures in premenopausal women may go undetected unless radiographs or vertebral assessment measurements are performed. In certain high-risk populations, such as young women with autoimmune disorders on high doses of glucocorticoids, the prevalence of vertebral fractures may be as high as 21 percent [58].

Later risk — A history of premenopausal fracture significantly increases the risk of a postmenopausal fracture. Data from the Study of Osteoporotic Fractures (SOF) demonstrate that women with a history of premenopausal fracture are 35 percent more likely to fracture during the postmenopausal years compared with women without a history of premenopausal fracture [35]. This relationship persists after controlling for a number of potential confounding variables. Other studies have reported similar findings [35,36,59,60]. These findings suggest that the risk of sustaining fractures may be a lifelong trait, probably reflecting the interaction of an individual's bone mass, bone quality, fall frequency, and neuromuscular protective response to falls [36].

ETIOLOGY — In premenopausal women, low bone mass and/or low-trauma fractures can sometimes be attributed to a secondary cause such as estrogen deficiency, glucocorticoid exposure, malabsorption, or hyperparathyroidism (table 1).

Low bone mass may be related to either inadequate peak bone mass acquisition and/or ongoing bone loss. Premenopausal women with low bone mass, no history of adult fracture, and no known secondary cause may or may not have a defect in bone strength.

Secondary causes — Some of the more common conditions that may cause low bone mass and/or fracture include the following:

Estrogen deficiency — Premenopausal estrogen deficiency from any cause is associated with bone loss or inadequate peak bone mass accrual. Examples include:

●Hypogonadotropic hypogonadism due to low weight, eating disorders, relative energy deficiency in sports (RED-S), hyperprolactinemia, and hypopituitarism. (See "Functional hypothalamic amenorrhea: Pathophysiology and clinical manifestations" and "Eating disorders: Overview of epidemiology, clinical features, and diagnosis" and "Clinical manifestations and evaluation of hyperprolactinemia".)

●Hypergonadotropic hypogonadism (premature ovarian insufficiency) due to various etiologies including chromosomal abnormalities such as Turner syndrome and fragile X syndrome, toxins such as chemotherapy and radiation, and autoimmune disease. (See "Management of primary ovarian insufficiency (premature ovarian failure)" and "Clinical manifestations and diagnosis of Turner syndrome", section on 'Osteoporosis and bone health' and "Evaluation and treatment of premenopausal osteoporosis".)

Drugs — Drugs that may be associated with bone loss in premenopausal women include glucocorticoids, some anticonvulsants, and depot medroxyprogesterone acetate. (See "Clinical features and evaluation of glucocorticoid-induced osteoporosis" and "Drugs that affect bone metabolism".)

Other — Many of the other risk factors for premenopausal osteoporosis are similar to those for postmenopausal osteoporosis and osteoporosis in men, including (table 1):

●Smoking.

●Inflammatory bowel disease. (See "Metabolic bone disease in inflammatory bowel disease".)

●Celiac disease. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults", section on 'Metabolic bone disorders'.)

●Cystic fibrosis. (See "Cystic fibrosis: Clinical manifestations and diagnosis", section on 'Musculoskeletal disorders'.)

●Previous or current hyperthyroidism. (See "Bone disease with hyperthyroidism and thyroid hormone therapy".)

●Hypercalciuria [61]. (See "Kidney stones in adults: Epidemiology and risk factors".)

●Hyperparathyroidism. (See "Primary hyperparathyroidism: Clinical manifestations", section on 'Skeletal'.)

●Depression has been associated with low bone mineral density (BMD) in premenopausal women [62-64]. However, the relationship between depression and osteoporosis is likely complex. Individuals with depression may have other risk factors for low bone mass, including medication use (antidepressants), hypercortisolism, and lifestyle factors including lower physical activity.

Normal pregnancy and lactation — Some studies suggest that pregnancy is associated with bone losses of approximately 3 to 5 percent at the spine and hip [65-67], while other studies have found that bone density remains stable during this period of increased calcium demand [68], or declines significantly only at the trochanter [69].

In contrast, lactation has more consistent and profound effects on bone density [70]. Bone loss of 3 to 10 percent at the spine and hip are seen over three to six months of lactation [67,71]. Bone loss is related to duration of lactation and duration of amenorrhea and is not prevented by calcium supplementation [72-74].

Parathyroid hormone-related protein (PTHrP), which is secreted by the lactating mammary gland, plays an important role in the control of calcium mobilization from bone during lactation in both humans and animals [70,75,76]. Estrogen deficiency that is characteristic of lactation may also be involved in the control of bone loss during this time.

Bone loss reverses during and after weaning [70]. Longitudinal studies in postpartum women show that recovery from lactation-associated bone loss may continue for 18 months or longer [73,77]. Studies in both humans and animal models suggest that the pattern and extent of bone recovery may be site specific, with complete reversal at the spine but incomplete or slower recovery at other sites [78]. Studies in animal models have also suggested that reproductive events lead to lasting microstructural skeletal changes that may be protective in the context of future menopausal bone loss [79]. Of note, most studies (including an analysis of data from the Women's Health Initiative Observational Study, sample size over 92,000) have not found an association between either parity (number of births) or lactation and osteoporosis or increased fracture risk in postmenopausal women in the United States or northern Europe [80-84].

These reproduction-related changes affect interpretation of bone density results. Care must be taken to obtain a detailed history regarding recent pregnancies and duration of lactation when interpreting bone density in a parous premenopausal woman. When bone density measurements are obtained around the time of pregnancy or lactation, it may be difficult to separate physiologic from pathophysiologic changes.

Pregnancy and lactation-associated osteoporosis — Pregnancy and lactation-associated osteoporosis (PLO) is a rare condition in which women typically present with painful fractures, often vertebral, in the third trimester of pregnancy or in the early postpartum period [85,86]. In a minority of cases, presentation with femoral neck fracture(s) during or after pregnancy has been described [87,88]. The overall incidence is estimated to be 0.4 cases per 100,000 women [70]. However, in a 20-year retrospective analysis of all cases of PLO (n = 16) at a single institution in Scotland, the incidence of PLO was estimated to be 6.8 cases per 100,000 pregnancies [89].

Several cohort studies documenting the clinical characteristics of PLO have reported that approximately 70 percent of women are primiparous and >75 percent have vertebral fractures, with an average of four to five fractures at presentation [86,87,89-93]. In a survey of 177 women with PLO, 93 percent reported vertebral fractures, with symptom onset during lactation in 79 percent and occurring on average at two months postpartum [87]. Several studies have documented very low BMD at the time of PLO presentation, with spine dual-energy x-ray absorptiometry (DXA) T- and Z-scores <-3.0 [86,87,92,93].

As this disorder is likely to be heterogeneous in its etiology and prognosis, a thorough evaluation for secondary causes of osteoporosis should be undertaken in all cases of PLO.

●Potential mechanisms and etiologies – Skeletal fragility in PLO may result from abnormal pregnancy-related changes in bone. Alternatively, women with preexisting skeletal fragility may manifest with fractures in the setting of the skeletal stress associated with a pregnancy and lactation [94,95].

Data from microarchitectural studies are consistent with the clinical presentation that commonly involves fractures at trabecular sites. In a study of seven primiparous women with PLO fractures, high-resolution peripheral quantitative computed tomography (HRpQCT) measurements showed marked trabecular microarchitectural deficits compared with healthy lactating controls [96].

The majority of case reports and case series find no known cause of osteoporosis in most women [87,90,91]. However, in a retrospective study of 52 women with PLO in France, 35 women (67 percent) had risk factors for low bone density either before or during the pregnancy [92]. Another retrospective cohort study found that 60 percent of women with PLO (10 of 16) had taken at least one medication that can contribute to osteoporosis, including low-molecular weight heparin and glucocorticoids [89]. In a survey study of 177 women with PLO, both heparin exposure (reported by 18 percent) and celiac disease (reported by 6 percent) were associated with more severe disease presentation [87].

An investigation of first-degree relatives of patients with PLO has suggested a strong genetic component [97], and family history of osteoporosis is reported by 30 to 50 percent of patients [87,89,92]. In a cohort of 42 women with PLO, gene panel screening found heterozygous variants classified as disease causing in eight women (19 percent) and heterozygous variants of interest in 21 (50 percent) [98]. Variants classified as disease causing were found in LRP5, WNT1, ALPL, COL1A1, COL1A2, and SLC34A3. Other studies have also documented variants in LRP5 and PLS3 in women with PLO [2,99,100].

It is notable that several variants found (LRP5, WNT1) are associated with a low bone turnover state. In a study examining bone remodeling rate at the tissue level (transiliac crest bone biopsies), women with PLO (studied more than one year postpartum at a time point that should reflect their baseline bone remodeling state) were found to have significantly lower bone remodeling rate in comparison with other premenopausal women with unexplained fractures and in comparison with healthy controls [101]. These findings suggest that abnormal osteoblast function or other bone formation defects may contribute to the pathophysiology of PLO.

●Long-term outcomes – Although some longitudinal studies report increases in spine and hip BMD over several years after the index pregnancy in women not receiving bone-specific therapy [102], studies also show an increased risk of fracture recurrence (overall and within the context of another pregnancy) [90]. In a study including 107 patients with PLO followed for a median of six years, 24 percent had subsequent fractures; the great majority of subsequent fractures were vertebral fractures, and number of fractures at diagnosis predicted subsequent risk [90]. Another study with 16.3-year follow-up of 20 women with PLO (average number of fractures 5.4) found that only 3 of the 20 women (15 percent) had subsequent fractures but all had severe physical and psychological distress at presentation. By two years after the fractures, symptoms had lessened but the majority of women were unable to return to work for 3.3 years [103]. Findings from a social media survey suggest that psychological stress from PLO can endure for many years. Participants in an online support group for women with PLO were compared with a control group of women without PLO using an online questionnaire. Most women with PLO expressed fear of fractures (18 of 24, or 67 percent) and fear of falling (15 of 24, or 56 percent) compared with only 0 and 2 percent of women, respectively, in the control group. Time from last pregnancy ranged from a few months up to eight years postpartum in both groups [104].

Idiopathic osteoporosis — Young women with bone fragility who lack secondary causes and disturbances in calcium metabolism are said to have "idiopathic osteoporosis" (IOP).

Two reports of IOP described the following clinical features [61,105]:

●Females and males were affected equally.

●A family history of osteoporosis was common.

●The mean age at diagnosis was approximately 35 years old.

●Fractures were usually multiple, occurring over a 5- to 10-year period, and involving sites rich in cancellous bone, such as the vertebrae. The hip was affected in approximately 10 percent of cases.

IOP is likely to be a heterogeneous disorder. Proposed mechanisms include osteoblast dysfunction and other forms of primary osteoporosis, abnormalities in the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis, subclinical estrogen deficiency, increased bone turnover, and hypercalciuria [10,61,105-110]. In a report of bone biopsy samples from women with IOP, bone remodeling was heterogeneous, with high, normal, and low bone formation rates seen [10]. Some women with IOP may have an unknown cause of bone loss and exhibit rapid bone metabolism, whereas others, with low bone formation rate, may have bone fragility due to inadequate peak bone mass acquisition without an active process of bone loss.

Among the women studied, those with the lowest bone formation rate had the most profound microarchitectural abnormalities. In one study of women with IOP, low bone formation rates were associated with higher body fat and higher IGF-1 levels [111]. The IGF-1 finding was unexpected since other forms of low turnover osteoporosis are associated with low IGF-1. The unexpected and paradoxical relationship between bone turnover and IGF-1 led to the hypothesis that atypical regulation of bone and fat may contribute to the mechanisms of osteoporosis in some women with IOP [111].

Genetic causes/primary osteoporosis — Some premenopausal women with unexplained fractures may represent a later presentation of a primary form of osteoporosis. Several conditions associated with abnormal skeletal development and bone fragility in childhood can have widely variable clinical presentations and degrees of severity. In rare instances, these conditions may lead to symptoms and/or diagnosis in early adulthood rather than childhood. Such conditions include osteogenesis imperfecta [112], hypophosphatasia (associated with osteomalacia), osteoporosis-pseudoglioma syndrome [99,100]/LRP5 mutations [113], Marfan syndrome, and Ehlers-Danlos syndrome. Age at presentation, severity of disease, and other clinical features may lead to evaluation for such primary causes of osteoporosis/fracture. (See "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders" and "Clinical manifestations and diagnosis of Ehlers-Danlos syndromes" and "Osteogenesis imperfecta: An overview".)

Mutational analysis in women with PLO, or in females and males with IOP presenting in young adulthood, has revealed rare or novel mutations (eg, LRP5/LRP6, COL1A1, and COL1A2, PLS3, WNT1, DKK1, FKBP10, HGD, SLC34A3) in selected patients [1,2,114,115]. In a whole exome sequencing study including 75 women with IOP or idiopathic low BMD, four women had likely pathogenic heterozygous variants found in LRP5 and PLS3 and four additional women had heterozygous variants of uncertain significance in FKBP10, SLC34A3, and HGD. The genetic findings are consistent with heterogeneous mechanisms for IOP; some findings were associated with very low bone remodeling while others were associated with high bone turnover and hypercalciuria or renal stones. It is also notable that no pathogenic genetic variants were found by whole exome sequencing in 89 percent of the subjects [2]. Further research is needed to identify additional genetic and nongenetic etiologies of IOP.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Osteoporosis".)

SUMMARY

●Definition – The relationship between fracture and low bone mass in premenopausal women is less certain than in postmenopausal women. Thus, the bone mineral density (BMD) criteria for diagnosis of osteoporosis in postmenopausal women do not generally apply to premenopausal women. Premenopausal women with a low-trauma fracture (aside from a fracture of the digits, skull, or face) may be considered to have osteoporosis (irrespective of BMD) only after other causes of fracture (eg, osteomalacia due to severe vitamin D deficiency, malignancy, other bone lesion) are excluded. (See 'Definitions' above.)

●Epidemiology – Low bone mass in premenopausal women may be due to suboptimal peak bone mass acquisition, ongoing bone loss, or both. The clinical significance of isolated low bone density in young women is unknown. However, a history of fracture in a premenopausal woman is associated with an increased risk of fracture later in life. (See 'Epidemiology' above.)

●Secondary causes – Low bone mass and/or low-trauma fractures in premenopausal women are usually attributable to other conditions (secondary causes) that predispose to osteoporosis. (See 'Secondary causes' above.)

●Pregnancy and lactation-associated osteoporosis – Pregnancy and lactation are states of high calcium demand and are associated with substantial expected and physiologic changes in bone mass. In some premenopausal women, early-onset osteoporosis presents in the context of the skeletal stress associated with pregnancy and lactation. This presentation is called pregnancy and lactation-associated osteoporosis (PLO). (See 'Pregnancy and lactation-associated osteoporosis' above.)

●Idiopathic osteoporosis – Idiopathic osteoporosis (IOP) describes the condition of low trauma fracture(s) in premenopausal women in the absence of an identifiable primary or secondary cause. Proposed mechanisms include osteoblast dysfunction, abnormalities in the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis, subclinical estrogen deficiency, increased bone turnover, and hypercalciuria. (See 'Idiopathic osteoporosis' above.)

●Genetic causes – In some cases, early-onset osteoporosis in a premenopausal woman may be related to primary or genetic forms of osteoporosis presenting in adulthood. Several studies have investigated potential genetic etiologies of both IOP and PLO. (See 'Genetic causes/primary osteoporosis' above.)